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(Circulation Research. 2007;100:1755.)
© 2007 American Heart Association, Inc.

Integrative Physiology

Cardiac Sympathetic Rejuvenation

A Link Between Nerve Function and Cardiac Hypertrophy

Kensuke Kimura, Masaki Ieda, Hideaki Kanazawa, Takashi Yagi, Makoto Tsunoda, Shin-ichi Ninomiya, Hiroyuki Kurosawa, Kenji Yoshimi, Hideki Mochizuki, Kazuto Yamazaki, Satoshi Ogawa, Keiichi Fukuda

From the Department of Regenerative Medicine and Advanced Cardiac Therapeutics (K.K., M.I., H. Kanazawa, T.Y., K.F.) and Cardiology Division (K.K., M.I., H. Kanazawa, T.Y., S.O.), Department of Internal Medicine, Keio University School of Medicine, Tokyo; Graduate School of Pharmaceutical Sciences (M.T.), Department of Bio-Analytical Chemistry, University of Tokyo; Research Planning Department (S.-i.N.), Daiichi Pure Chemicals Co Ltd, Ibaraki; Biology Laboratory Research Center (H. Kurosawa), Daiichi Radioisotope Laboratories Ltd, Chiba; Fujimoto Pharmaceutical Research Inc (K. Yoshimi), Osaka; Department of Neurology (H.M.), Juntendo University School of Medicine, Tokyo; and Department of Pathology (K. Yamazaki), Saiseikai Central Hospital, Tokyo, Japan.

Correspondence to Keiichi Fukuda, MD, PhD, Department of Regenerative Medicine and Advanced Cardiac Therapeutics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail kfukuda{at}sc.itc.keio.ac.jp

Neuronal function and innervation density is regulated by target organ-derived neurotrophic factors. Although cardiac hypertrophy drastically alternates the expression of various growth factors such as endothelin-1, angiotensin II, and leukemia inhibitory factor, little is known about nerve growth factor expression and its effect on the cardiac sympathetic nerves. This study investigated the impact of pressure overload-induced cardiac hypertrophy on the innervation density and cellular function of cardiac sympathetic nerves, including kinetics of norepinephrine synthesis and reuptake, and neuronal gene expression. Right ventricular hypertrophy was induced by monocrotaline treatment in Wistar rats. Newly developed cardiac sympathetic nerves expressing ß₃-tubulin (axonal marker), GAP43 (growth-associated cone marker), and tyrosine hydroxylase were markedly increased only in the right ventricle, in parallel with nerve growth factor upregulation. However, norepinephrine and dopamine content was paradoxically attenuated, and the protein and kinase activity of tyrosine hydroxylase were markedly downregulated in the right ventricle. The reuptake of [¹²⁵I]-metaiodobenzylguanidine and [³H]-norepinephrine were also significantly diminished in the right ventricle, indicating functional downregulation in cardiac sympathetic nerves. Interestingly, we found cardiac sympathetic nerves in hypertrophic right ventricles strongly expressed highly polysialylated neural cell adhesion molecule (PSA-NCAM) (an immature neuron marker) as well as neonatal heart. Taken together, pressure overload induced anatomical sympathetic hyperinnervation but simultaneously caused deterioration of neuronal cellular function. This phenomenon was explained by the rejuvenation of cardiac sympathetic nerves as well as the hypertrophic cardiomyocytes, which also showed the fetal form gene expression.

Key Words: sympathetic nervous system • norepinephrine • pulmonary hypertension • rejuvenation

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